The Metabotropic Glutamate Receptor System Protects against Ischemic Free Radical Programed Cell Death in Rat Brain Endothelial Cells

Lin, Shi-Hua; Maiese, Kenneth

doi:10.1097/00004647-200103000-00010

Cited by 89 publications

(159 citation statements)

References 49 publications

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“…Neurons and glia are commonly recognized as the major targets for glutamate in the brain, but the existence of functional GluRs in cerebral vasculature has been long debated. However, the vast body of evidence accumulated over the recent years clearly demonstrates that GluRs are expressed in cerebral vascular endothelium and contribute to the endothelial functions in rats, humans, and newborn pigs [61,[84][85][86][87][88].…”

Section: Glutamate Receptors In Cerebral Vascular Endothelium and Ho-mentioning

confidence: 99%

Cerebroprotective Functions of HO-2

Parfenova¹,

Leffler²

2008

CPD

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The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via posttranslational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, the end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BK Ca channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of BK Ca channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidantgenerating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilirubin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an effective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress. KeywordsHeme oxygenase; cerebral protection; cerebrovascular disease; oxidative stress; seizures; carbon monoxide; bilirubin Vasodilator role of CO in cerebral circulation A. Vasoactive effects of exogenous CO in cerebral vesselsExperimental studies in newborn pigs conducted using in vivo and in vitro approaches demonstrate that exogenous CO is a potent vasodilator in cerebral circulation [1][2][3][4][5][6][7]. CO can be delivered to the brain as CO gas dissolved in a physiological buffer or as recently introduced CO-releasing molecules (CO-RMs) that release CO on illumination (dimanganese decacarbonyl, DMDC) or when dissolved in physiologically buffered solutions (sodium boranocarbonate, CO-RM-A1) [8,9]. In vivo, CO, DMDC and CORM-A1 applied directly to the brain surface under the cranial window at concentrations ≥10 −7 M causes dilation of pial arterioles, major resistance brain vessels that define the cerebral blood

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Section: Glutamate Receptors In Cerebral Vascular Endothelium and Ho-mentioning

confidence: 99%

Cerebroprotective Functions of HO-2

Parfenova¹,

Leffler²

2008

CPD

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“…Furthermore, oxidative stress can significantly increase chromosomal aberrations and micronuclei [26,39] and lead to the activation of apoptotic pathways in ECs [38,116,193]. ECs that are exposed to oxidative stress incur both DNA fragmentation and membrane PS externalization during exposure to insults, such as hypoxia, oxidants, and free radicals [9,28,38,39,124].…”

Section: Alzheimer's Disease In the Aging Populationmentioning

confidence: 99%

“…Cytoprotection by the mGluR system is believed to act at or below the level of free radical generation and oxidative stress [143,192,236]. More recent work has suggested that mGluR offers similar protective capacity to the vascular system by preventing endothelial cell DNA degradation, caspase activity, and inhibiting a thrombotic state through the maintenance of membrane asymmetry [125,124,142].…”

Section: Modulation Of the Metabotropic Glutamate Systemmentioning

confidence: 99%

“…The process is blocked by the administration of (+)-α-methyl-4-carboxyphenylglycine, a non-selective antagonist of group I/II mGluRs [228]. Activation of group III mGluRs has also been shown to protect neurons against microglial neurotoxicity during Aβ application [218] that may be a result of the regulation of caspase activity [43,124]. Under some circumstances, diminished activity of mGluRs may prove useful for cellular protection.…”

Section: Modulation Of the Metabotropic Glutamate Systemmentioning

confidence: 99%

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Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

Chong

Maiese

2005

Brain Research Reviews

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135

121

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More than a century has elapsed since the description of Alois Alzheimer's patient Auguste D. Yet, the well-documented generation of β-amyloid aggregates and neurofibrillary tangles that define Alzheimer's disease is believed to represent only a portion of the cellular processes that can determine the course of Alzheimer's disease. Understanding of the complex nature of this disorder has evolved with an increased appreciation for pathways that involve the generation of reactive oxygen species and oxidative stress, apoptotic injury that leads to nuclear degradation in both neuronal and vascular populations, and the early loss of cellular membrane asymmetry that mitigates inflammation and vascular occlusion. Recent work has identified novel pathways, such as the Wnt pathway and the serine-threonine kinase Akt, as central modulators that oversee cellular apoptosis and the formation of neurofibrillary tangles through their downstream substrates that include glycogen synthase kinase-3β, Bad, and Bcl-x L . Other closely integrated pathways control microglial activation, release of inflammatory cytokines, and caspase and calpain activation for the processing of amyloid precursor protein, tau protein cleavage, and presenilin disposal. New therapeutic avenues that are just open to exploration, such as with nicotinamide adenine dinucleotide modulation, cell cycle modulation, metabotropic glutamate system modulation, and erythropoietin targeted expression, may provide both attractive and viable alternatives to treat Alzheimer's disease.

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“…Furthermore, oxidative stress can significantly increase chromosomal aberrations and micronuclei (Bresgen, N et al, 2003 and lead to the activation of apoptotic pathways , Lee, DH et al, 2002 in ECs. ECs that are exposed to oxidative stress incur both DNA fragmentation and membrane PS externalization during exposure to insults, such as hypoxia, oxidants, and free radicals (Aoki, M et al, 2001, Burlacu, A et al, 2001, Lin, SH and Maiese, K, 2001). …”

Section: Oxidative Stress and Alzheimer's Diseasementioning

confidence: 99%

Employing New Cellular Therapeutic Targets for Alzheimers Disease: A Change for the Better?

Chong¹,

Li²,

Maiese³

2005

CNR

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Alzheimer's disease is a progressive disorder that results in the loss of cognitive function and memory. Although traditionally defined by the presence of extracellular plaques of amyloid-β peptide aggregates and intracellular neurofibrillary tangles in the brain, more recent work has begun to focus on elucidating the complexities of Alzheimer's disease that involve the generation of reactive oxygen species and oxidative stress. Apoptotic processes that are incurred as a function of oxidative stress affect neuronal, vascular, and monocyte derived cell populations. In particular, it is the early apoptotic induction of cellular membrane asymmetry loss that drives inflammatory microglial activation and subsequent neuronal and vascular injury. In this article, we discuss the role of novel cellular pathways that are invoked during oxidative stress and may potentially mediate apoptotic injury in Alzheimer's disease. Ultimately, targeting new avenues for the development of therapeutic strategies linked to mechanisms that involve inflammatory microglial activation, cellular metabolism, cell-cycle regulation, G-protein regulated receptors, and cytokine modulation may provide fruitful gains for both the prevention and treatment of Alzheimer's disease. Keywordsβ-Amyloid; Akt; caspases; erythropoietin; Forkhead transcription factors; metabotropic; microglia; nicotinamide; Wnt PATHOPHYSIOLOGY AND MEDICAL IMPLICATIONS OF ALZHEIMER'S DISEASENeuronal injury during Alzheimer's disease predominantly occurs in the hippocampus and the cortex. The disorder leads to a progressive deterioration of cognitive function with loss of memory and is characterized by two pathologic hallmarks that consist of extracellular plaques of amyloid-β peptide aggregates and intracellular neurofibrillary tangles composed of hyperphosphorylated microtubular protein tau. The β-amyloid deposition that constitutes the plaques is composed of a 39−42 amino acid peptide (Aβ), which is the proteolytic product of the amyloid precursor protein (APP) .With an aging population, medical costs for neurodegenerative disease parallel a progressive loss of economic productivity with increasing morbidity and mortality. The cost of physician

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The Metabotropic Glutamate Receptor System Protects against Ischemic Free Radical Programed Cell Death in Rat Brain Endothelial Cells

Cited by 89 publications

References 49 publications

Cerebroprotective Functions of HO-2

Cerebroprotective Functions of HO-2

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

Employing New Cellular Therapeutic Targets for Alzheimers Disease: A Change for the Better?

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